GluN2A

- Radiprodil appeared to be generally well-tolerated in patients with gain-of-function (GoF) variants in GRIN genes, both with and without countable motor seizures (CMS) at baseline - Patients with CMS saw a median reduction of 86% in seizure frequency from baseline, over and above background anti-seizure medications, with 71% experiencing a greater than 50% reduction - Results are expected to support planned discussions with regulators to potentially advance radiprodil to a Phase 3 pivotal trial - GRIN Therapeutics is backed by a $200 million capital commitment from Blackstone Life Sciences NEW YORK, Sept. 9, 2024 /PRNewswire/ -- GRIN Therapeutics, Inc., a leader in the development of therapies to treat serious neurodevelopmental disorders, reported topline results from the Company's ongoing two-part global Phase 1b open-label trial evaluating the safety, tolerability, pharmacokinetics, and efficacy of radiprodil, an investigational, selective and potent negative allosteric modulator of the N-methyl-D-aspartate receptor subtype 2B (NR2B or GluN2B), in the treatment of GRIN-related neurodevelopmental disorder. The results were presented in a podium presentation yesterday at the International League Against Epilepsy (ILAE) 15th European Epilepsy Conference in Rome, Italy. "The results of this trial are very encouraging as they suggest that radiprodil has the potential to substantially reduce the occurrence of seizures and possibly improve behaviors in children with gain-of-function mutations who are not responding well to current treatments," said Prof. Renzo Guerrini, MD, FRCP, FAES, Director, Neuroscience and Human Genetics Department, Phase 1 Clinical Trial Centre, Children's Hospital A. Meyer IRCCS, University of Florence, Italy. "Given these initial efficacy data and promising safety profile, we look forward to continuing to advance this important research program into the next phase of development." The Honeycomb study enrolled 15 pediatric patients with confirmed GoF mutations in the GRIN1, GRIN2A, or GRIN2B genes. The primary objectives of the study were to assess the safety and pharmacokinetics of radiprodil, while key secondary objectives focused on evaluating efficacy on both seizures and non-seizure outcomes. At study enrollment, patients were divided into two cohorts based on the frequency of countable motor seizures (CMS) they experienced during a 28-day screening period (Cohort 1) and baseline severity of non-seizure behavioral symptoms (Cohort 2). Following screening and observation periods, patients were escalated from a starting dose level of 0.05 mg/kg based on tolerability, pharmacokinetics, and predicted GluN2B receptor occupancy to a dose level to be maintained through an eight-week maintenance period. Part B of the Honeycomb study, an open-label extended treatment period for patients who completed Part A and were eligible for continued study treatment, remains ongoing. As of the July 15 data cut, 15 patients were available for analysis. Demographics and baseline disease characteristics were representative of the targeted GRIN population and generally balanced between the seizure (Cohort 1) and non-seizure behavior (Cohort 2) cohorts. There was a high level of seizure activity at baseline in Cohort 1 with a mean of 37.0 and a median of 25.5 CMS per patient (range of 4.8 to 85.9). There were zero CMS at baseline in Cohort 2. Radiprodil appeared generally well tolerated throughout Part A and B of the study to date. The treatment-emergent adverse events (TEAEs) most commonly observed (i.e., in three or more patients) were those associated with infections or underlying disease symptoms including pyrexia, diarrhea, respiratory tract infection, abnormal behavior, agitation, cough, dystonia, fatigue, and gastroenteritis. There were no deaths in the study. Three patients experienced a serious adverse event (one patient each with obstructive bronchitis, viral pneumonia, or adenovirus infection). None were considered related to treatment with radiprodil and none met study stopping rule criteria. During Part A of the study, patients treated with radiprodil showed a median reduction of 86% in seizure frequency versus baseline, which was a key secondary endpoint in the trial. During this same period, 71% of patients had a greater than 50% reduction in CMS, with 43% seeing a greater than 90% reduction and one patient being seizure free. Clinicians and caregivers also generally assessed patients as improved clinically over the course of the study. "We believe the findings from the Honeycomb study in gain-of-function patients with treatment resistant symptoms provide strong rationale to progress this promising program into Phase 3 development as quickly as possible," said Bruce Leuchter, MD, President and Chief Executive Officer at Neurvati Neurosciences and GRIN Therapeutics. "I am proud of the progress we have made to address the profound unmet need in GRIN-related neurodevelopmental disorder since we launched the company three years ago with an investment from Blackstone Life Sciences. These compelling data represent the first major milestone in our development plans for radiprodil and will help us build new levels of momentum toward achieving our goal of bringing the first approved treatment to patients living with GRIN-related neurodevelopmental disorder." About GRIN-related neurodevelopmental disorder: GRIN-related neurodevelopmental disorder is a family of rare, genetically defined pediatric neurodevelopmental disorders caused by mutations in GRIN genes. While symptoms of GRIN-related neurodevelopmental disorder can present as early as infancy, a diagnosis is often not confirmed until age two or later when a child fails to reach developmental milestones. Individuals may experience developmental delay, intellectual disabilities, epilepsy, muscular hypotonia, movement disorders, spasticity, feeding difficulties and behavioral problems. There are currently no approved therapies for GRIN-related neurodevelopmental disorder. About Radiprodil: Radiprodil is an investigational, selective and potent negative allosteric modulator of the N-methyl-D-aspartate receptor subtype 2B (NR2B or GluN2B). In nonclinical studies, radiprodil has been shown to potently and selectively modulate the N-methyl-D-aspartate (NMDA) receptor subtype 2B (NR2B or GluN2B). Radiprodil has also demonstrated an antiseizure effect in a number of in vitro and in vivo preclinical seizure and epilepsy models and specifically in models characterized by an enhanced GluN2B-NMDA transmission, which can occur with gain-of-function (GoF) mutations in GRIN-related disorder. About GRIN Therapeutics: GRIN Therapeutics is dedicated to the research and development of precision therapeutics for pediatric neurodevelopmental disorders with the goal of bringing hope to patients and caregivers. Working to develop the investigational product radiprodil as a novel therapy for patients with neurodevelopmental disorders, the company has two ongoing clinical trials to evaluate radiprodil for the potential treatment of GRIN-related neurodevelopmental disorder and other neurological conditions including tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD) type II. GRIN Therapeutics is an affiliate of Neurvati Neurosciences, a portfolio company of Blackstone Life Sciences (BXLS). For more information, please visit About Neurvati Neurosciences Neurvati Neurosciences, a portfolio company of Blackstone Life Sciences, identifies and advances the development of high-potential drug candidates across the neuroscience landscape. Neurvati employs a collaborative model that establishes fit-for-purpose affiliate companies, aligning dedicated resources with long-term strategic capital to catalyze innovative treatment options in areas of unmet need. Neurvati's team of experienced operators and drug developers seeks opportunities to challenge current treatment paradigms and make a difference for patients suffering from a wide range of neurological and psychiatric disorders. For more information, please visit . About Blackstone Life Sciences Blackstone Life Sciences is an industry-leading private investment platform with capabilities to invest across the life cycle of companies and products within key life science sectors. By combining scale investments and hands-on operational leadership, Blackstone Life Sciences helps bring to market promising new medicines and medical technologies that improve patients' lives and currently has more than $9 billion in assets under management. Corporate Contact: Elliott Ruiz +1 201.674.5417 [email protected] SOURCE GRIN Therapeutics Inc.

Milestone represents initiation of first-ever clinical trial using NR2B-negative allosteric modulator to treat GRIN-related disorders NEW YORK--(BUSINESS WIRE)-- GRIN Therapeutics Inc., a leader in development of therapies to treat GRIN-related disorders, today announced that the first patient has been dosed in the Honeycomb Study, the Company’s Phase 1B clinical trial of radiprodil, an investigational NR2B-negative allosteric modulator in development for the treatment of GRIN-related disorders. Radiprodil targets the hyperactive receptors associated with the development and progression of GRIN-related disorders by potently and selectively modulating the Nmethyl-D-aspartate (NMDA) receptor subtype 2B (NR2B). “GRIN-related disorders represent a significant area of unmet need in healthcare and the initiation of the Honeycomb Study is a historic milestone for GRIN Therapeutics and for patients around the world who are in desperate need of new treatments,” said Michael A. Panzara, M.D., MPH, chief medical officer of Neurvati Neurosciences, the parent company of GRIN Therapeutics. “We continue to be inspired by the children and families affected by GRIN-related disorders and by the leaders from the treatment community who have supported this important research and are very grateful for their partnership.” GRIN-related disorders are genetically defined, rare pediatric developmental and epileptic encephalopathies (DEEs) caused by mutations in the gene coding on the NMDA glutamate receptor. People living with GRIN-related disorders present with a spectrum of symptoms including epilepsy, behavioral disorders, autism, intellectual disability, and movement disorders. Currently, there are no disease-specific treatment options for GRIN-related disorders. Radiprodil is a small molecule that selectively targets NR2B-NMDA receptors that are overactive in GRIN-related disorders and that represent important potential targets in effective therapeutic intervention. “When we identified the genes that cause GRIN-related disorders in 2014, we never imagined the collaboration that would be undertaken to get into the clinic so quickly,” stated Johannes Lemke, M.D., Head of Leipzig University Hospitals' Institute of Human Genetics. “Working together with GRIN Therapeutics to evaluate radiprodil in patients with GRIN-related disorders represents an important advancement and I look forward to the study results with anticipation and optimism.” The open label Honeycomb phase 1B study will evaluate the safety, tolerability, pharmacokinetics, and effects on seizures, behavioral symptoms, sleep, and motor functions of multiple individually titrated doses of radiprodil in children with GRIN-related disorders. The trial will include up to 24 participants between the ages of six months and 12 years with confirmed gain-of-function (GoF) variants causing GRIN-related disorders, including variants on GRIN2B, GRIN2A, GRIN2D, and GRIN1. The trial will include one cohort of patients who have experienced drug resistant seizures with a frequency of at least once weekly and a second cohort including patients with behavioral and other symptoms who have experienced fewer or no seizures. The study will consist of a screening period, a titration period, and a maintenance period on the highest tolerated dose. Upon completion of treatment, participants will have the option to enter a long-term extension study. About Radiprodil: Radiprodil is an investigational, selective negative allosteric modulator of the Nmethyl-D-aspartate receptor subtype 2B (NR2B). It has been shown to inhibit NMDA glutamate currents when tested using receptors containing NR2B subunits coded by gain of function (GoF) mutations in the GRIN2B and GRIN2A genes, which are known to cause GRIN-related disorders. (Mullier et al 2017; Han et al 2021). About GRIN Therapeutics: GRIN Therapeutics is a life sciences company working to develop the investigational product radiprodil as a novel therapy for patients diagnosed with GRIN-related disorders. The company has initiated the Honeycomb phase 1 clinical trial to assess the safety and efficacy of radiprodil in the treatment of GRIN-related disorders. About Neurvati Neurosciences Neurvati Neurosciences is a Blackstone Life Sciences portfolio company established to advance development of high-potential technologies to address a broad range of unmet needs in the treatment of neurological and psychiatric disorders. Neurvati’s collaborative model supports rapid late-stage development of innovative treatments supported by robust pre-clinical and clinical data across the neuroscience landscape to improve the lives of patients. The Neurvati team is driven by a deep understanding of all phases of drug development and the regulatory and commercialization processes associated with therapies to treat brain and nervous system diseases. For more information, please visit neurvati.com.

Neumora Therapeutics has made some changes to its pipeline since it burst onto the scene one year ago. One year after its splashy $500 million unveiling, Neumora Therapeutics is back with a series B to keep its multiprogram neuroscience pipeline moving toward and through the clinic. The series B syndicate has put up $112 million, a sum that is big by most standards but dwarfed by the biotech’s first round. Neumora has raised around $650 million to date to test the idea that the precision medicine advances that have transformed oncology are now ready to redefine how neurological diseases are treated. As has happened in cancer, neuroscience could shift from a broad-brush approach that has lackluster outcomes because of patient heterogeneity to a more targeted paradigm that zeros in on likely responders. Arch Venture Partners led the series A, which included a $100 million investment from Amgen. Both Arch and Amgen have returned for the series B, joining with fellow existing investors including F-Prime Capital and Invus and new backers such as Abu Dhabi Growth Fund to funnel $112 million into Neumora. The money will support the development of a pipeline that is led by NMRA-140, a KOR antagonist in phase 2 development as a treatment for depression. Neumora completed a 204-patient phase 2a trial of the candidate in adults with major depressive disorder and symptoms of anhedonia, the inability to feel pleasure in normally pleasurable activities, over the summer.  Neumora has made some changes to its pipeline since it burst onto the scene one year ago. In February, the biotech struck a deal with Vanderbilt University to secure global rights to a M4 muscarinic receptor positive allosteric modulator program. The program, now called NMRA-M4R, is one of two projects that are closing in on the clinic.  The neuroscience startup has also removed two programs from its pipeline, including one that was listed as its third most advanced project at the time of the series A. One year ago, NMRA-094, a drug designed to treat sleep disorders by acting on histamine and serotonin receptors, was moving through preclinical. The candidate is now absent from Neumora’s publicly disclosed pipeline.  NMRA-094 is joined on the cutting-room floor by NMRA-GRIN2B, which Neumora previously listed as a discovery-stage treatment for neuropsychiatric disorders. The biotech is continuing to develop a therapy designed to act on GRIN2A.